Despite many advances in biomedical research, viral infections remain a major threat to human health. In the past 20 years we have witnessed either the emergence or the definition of acute and persistent viral infections caused by agents such as HIV, HTLV, hepatitis viruses, ebola virus, hantavirus, papillomavirus, herpesviruses 6-8, the SARS coronavirus, and monkeypox, and we continue to live with the specter of the re-emergence of a 1918-like strain of influenza virus or the release of variola (small pox) virus by bioterrorism. There are few effective antiviral drugs to combat these viruses, and protection from these agents mainly rests on public health containment measures and on the use and development of vaccines. It is now thought that attenuated viruses which induce CD8 T cell responses, as well as antibody, make better, longer lasting vaccines. Thus, it is important to understand factors contributing to the maintenance or loss of CD8 memory in an environment in which a host is continually challenged by pathogens that may sometimes become persistent. The CD8 T cell response to viral infections is highly dynamic, beginning with a cytokine driven apoptotic loss (lymphopenia) in memory CD8 T cell number in the early stages of infection, followed by a dramatic expansion in number of virus-specific T cells and then by a second decline or silencing phase, associated with T cell apoptosis and dissemination into peripheral tissues. The activated CD8 T cells during the acute response also become sensitized to undergo Fas/FasL-mediated activation-induced cell death (AICD) on strong signaling through their TCR, and this may contribute to the transient immune deficiencies seen during viral infections and to the clonal exhaustion of T cells under conditions of antigen excess. My lab has made the unique observations that (1) there is a cytokine-driven apoptosis early in infection, that (2) apoptosis of CD8 T cells is differentially regulated, dependent on the tissue site, and that (3) there is substantial attrition of memory CD8 T cells occurring as a consequence of acute or persistent infections with unrelated viruses. Here we propose to continue our studies on CD8 T cell apoptosis in mice infected with LCMV, Pichinde, and vaccinia viruses, and determine (1) the mechanism and significance of the early cytokine-induced lymphopenia and apoptosis of memory CD8 T cells during viral infections, (2) the mechanisms regulating the tissue-dependent differences in apoptosis of virus-specific CD8 T cells, and (3) the mechanism and significance of memory T cell attrition following acute and persistent viral infections.